Validación

Essentials of Pharmaceutical Chemistry

Essentials of Pharmaceutical Chemistry
Third edition

Donald Cairns
BSc, PhD, CSci, CChem, MRPharmS, MRSC Associate Head of School of Pharmacy The Robert Gordon University Aberdeen, UK

London

•

Chicago

Published by the Pharmaceutical Press An imprint of RPS Publishing 1 Lambeth High Street, London SE1 7JN, UK 100 South Atkinson Road,Suite 200, Grayslake, IL 60030–7820, USA © Pharmaceutical Press 2008 is a trade mark of Pharmaceutical Press First edition published 2000 Second edition published 2003 Third edition published 2008 Typeset by J&L Composition, Filey, North Yorkshire Printed in Great Britain by TJ International, Padstow, Cornwall ISBN 978 0 85369 745 9 All rights reserved. No part of this publication may bereproduced, stored in a retrieval system, or transmitted in any form or by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or liability for any errors or omissions that may be made. The right of Donald Cairns tobe identified as the author of this work has been asserted by him in accordance with the Coypright, Designs and Patents Act, 1988. A catalogue record for this book is available from the British Library

For Elaine, Andrew and Mairi

Contents

Preface to the third edition xi Acknowledgements xiii About the author xv

1

Chemistry of acids and bases
Dissociation of weak acids and bases 3Hydrolysis of salts 9 Amphiprotic salts 11 Buffer solutions 11 Buffer capacity 14 Biological buffers 16 Ionisation of drugs 19 pKa values of drug molecules 20 pH indicators 20 Tutorial examples 23 Problems 28

1

2

Partition coefficient and biopharmacy
Experimental measurement of partition coefficient 33 Drug absorption, distribution and bioavailability 36 Passive diffusion 39 The pHpartition hypothesis 40 Active transport mechanisms 44 The action of local anaesthetics 45 Excretion and reabsorption of drugs 48 Food and drink 50 Tutorial examples 51 Problems 56

29

viii Contents
3 Physicochemical properties of drugs
Carboxylic acids 59 Phenols 63 Warfarin 64 Phenylbutazone 67 Indometacin 67 Barbiturates 67 Phenytoin 69 Sulfonamides 69 Basic drugs 71 Basicity of heterocycliccompounds 73 Separation of mixtures 73 Tutorial examples 75 Problems 79

59

4

Stereochemistry
Polarimetry 84 Biological systems 88 Fischer projections 89 Stereochemistry case study: thalidomide 97 Geometrical isomerism 99 Tutorial examples 101 Problems 103

83

5

Drug metabolism
Metabolic pathways 106 Cytochromes P450 107 Enzyme induction and inhibition 111 Drug conjugationreactions (Phase 2) 112 Stereochemistry 119 Metabolic pathways for common drugs 120 Tutorial example 128 Problems 130

105

6

Volumetric analysis of drugs
Volumetric flask 134 Pipette 134 Burettes 135 Units of concentration 135

133

Contents
Concentration of active ingredients 138 Design of an assay 138 Practical points 141 Back and blank titrations 144 Assay of unit-dose medicines 147Non-aqueous titrations 149 REDOX titrations 150 Compleximetric titrations 152 Argentimetric titrations 154 Limit tests 154 Problems 155

ix

7

Analytical spectroscopy
Effect of pH on spectra 164 Instrumentation 168 Experimental measurement of absorbance 170 Dilutions 171 Quantitative aspects of spectroscopy 172 Beer’s and Lambert’s laws 173 Methods of drug assay 175 Derivative spectroscopy177 Infrared spectroscopy 179 Fluorimetry 182 Structure elucidation 183 Tutorial examples 193 Problems 201

159

8

Stability of drugs and medicines
Oxidation 205 Stability of free radicals 207 Prevention of oxidative deterioration 211 Autoxidation of fats and oils 215 Ageing 216 Hydrolysis 217 Examples of drugs susceptible to hydrolysis 220 Other mechanisms of degradation 222 Prodrugs 223...